Rheumatoid Arthritis: Sattar N

Choy E, Sattar N. · Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King's College, London, UK. · Ann Rheum Dis. · Pubmed #19286905 No free full text.

Abstract: In severe untreated rheumatoid arthritis (RA), reductions in high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and total cholesterol have been noted; this is in line with findings in other pathologies/conditions associated with inflammation or infection, such as sepsis, cancer, trauma or the postoperative period. Although the precise mechanisms remain to be established, cytokine-induced activation of the reticuloendothelial system is potentially critical to such changes. Consequently, dampening of inflammation in severe RA-as occurs with several biologics-may lead to increases, not only in high-density lipoprotein-cholesterol, but also with other lipid moieties, including total and low-density lipoprotein-cholesterol and, perhaps, triglycerides. This concept is consistent with findings following antitumour necrosis factor treatment and interleukin-6 receptor inhibition in patients with RA. At the same time, it is increasingly apparent that potent dampening of inflammation, however achieved, broadly reduces the risk of cardiovascular disease in RA. Therefore, changes in lipid profiles, particularly increases in cholesterol and triglycerides that occur with treatments for severe inflammation, may not represent increased cardiovascular risk as in the usual understanding of lipid-level elevations in individuals without significant inflammation. Rather, changes in lipid levels, in part or largely, may represent a predictable response to attenuation of inflammation. These observations are increasingly important clinically and should aid in the understanding and interpretation of lipid changes under inflammatory conditions, as well as in the context of potent anti-inflammatory interventions.

Sattar N, McInnes IB. · Section of Vascular Biochemistry, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow Royal Infirmary, Scotland, UK. · Curr Opin Rheumatol. · Pubmed #15838238 No free full text.

Abstract: PURPOSE OF REVIEW: To summarise recent evidence for elevated risk of coronary heart disease (CHD) in rheumatoid arthritis (RA) and explore explanatory mechanisms and modalities that may lessen such risk. RECENT FINDINGS: Evidence for elevated CHD risk in RA is convincing. On current estimates, individuals who have had RA for several years have around a twofold higher risk for CHD compared with non-RA persons after taking account of most traditional risk factors. Such excess risk appears to be driven by systemic inflammation both directly via its deleterious effects on blood vessels (endothelial dysfunction inclusive of myocardial microvascular abnormalities) and indirectly by its accentuation of multiple risk pathways including lipid abnormalities. Established therapies that lessen RA disease activity and systemic inflammation will likely lessen CHD risk, although there remains considerable scope for more robust studies employing better measures of vascular disease (e.g., carotid intima-media thickening). Other emerging evidence indicates statins may have dual effects in RA, with a modest disease-modifying effect (requiring confirmation) and significant lipid-lowering action. The latter finding is particularly important because extrapolation of data from all statin endpoint trials suggests that the extent of low-density lipoprotein cholesterol reduction may account for most statin clinical benefit. SUMMARY: Systemic inflammation is the major driver for excess vascular comorbidity in RA. Controlling systemic inflammation should lessen vascular risk but complete, long-term suppression of articular inflammation is rarely achieved. Thus, the use of conventional CHD risk reduction strategies, in particular statins, should be considered in patients with RA with prevalent CHD or at elevated risk.

McCarey DW, Sattar N, McInnes IB. · Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK. · Arthritis Res Ther. · Pubmed #15743490 links to  free full text

Abstract: Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.

McInnes IB, McCarey DW, Sattar N. · Centre for Rheumatic Diseases, Department of Vascular Biochemistry, University of Glasgow, UK. · Ann Rheum Dis. · Pubmed #15547075 links to  free full text

This publication has no abstract.

Sattar N, McCarey DW, Capell H, McInnes IB. · Department of Pathological Biochemistry and Centre for Rheumatic Diseases, North Glasgow Hospitals University NHS Trust, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Circulation. · Pubmed #14676136 links to  free full text

Abstract: There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.

Datta D, Ferrell WR, Sturrock RD, Jadhav ST, Sattar N. · Centre for Rheumatic Diseases, Royal Infirmary, Glasgow, United Kingdom. · Atherosclerosis. · Pubmed #16806231 No free full text.

Abstract: Rheumatoid arthritis (RA) is associated with greater risk of cardiovascular morbidity and mortality, the inflammatory component of RA being strongly linked to this excess risk. Endothelial dysfunction is linked to atherosclerosis and has been demonstrated in larger vessels in RA. In this pilot study, we determined for the first time whether skin microvascular function was impaired in patients with active RA and also determined its response to anti-inflammatory treatment. This was assessed non-invasively using laser Doppler imaging combined with iontophoresis of the vasodilators acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent) to the forearm. Eight RA patients admitted for acute flare-ups were assessed before and following anti-inflammatory treatment. Standard laboratory indices were obtained along with pain perception (VAS). A control group of eight subjects was included for baseline comparison. Compared to this group, vascular function was substantially and significantly (P<0.00001) lower in RA patients. Following treatment, as CRP and VAS decreased, vascular function improved for both ACh (P<0.00001) and SNP (P=0.001), this improvement being significantly greater for ACh (P<0.001). Vascular dysfunction is evident in RA patients, even at the level of the cutaneous microcirculation, but improves as inflammation regresses. Assessment of cutaneous vascular function may be a useful, non-invasive surrogate indicator of vascular risk in RA, inclusive of myocardial microvascular abnormalities.

McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N. · Centre for Rheumatic Diseases, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK. · Lancet. · Pubmed #15207950 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis is characterised by inflammatory synovitis, articular destruction, and accelerated atherogenesis. HMG-CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitors (statins) mediate clinically significant vascular risk reduction in patients without inflammatory disease and might have immunomodulatory function. We postulated that statins might reduce inflammatory factors in rheumatoid arthritis and modify surrogates for vascular risk. METHODS: 116 patients with rheumatoid arthritis were randomised in a double-blind placebo-controlled trial to receive 40 mg atorvastatin or placebo as an adjunct to existing disease-modifying antirheumatic drug therapy. Patients were followed up over 6 months and disease activity variables and circulating vascular risk factors were measured. Coprimary outcomes were change in disease activity score (DAS28) and proportion meeting EULAR (European League Against Rheumatism) response criteria. Analysis was by intention to treat. FINDINGS: At 6 months, DAS28 improved significantly on atorvastatin (-0.5, 95% CI -0.75 to -0.25) compared with placebo (0.03, -0.23 to 0.28; difference between groups -0.52, 95% CI -0.87 to -0.17, p=0.004). DAS28 EULAR response was achieved in 18 of 58 (31%) patients allocated atorvastatin compared with six of 58 (10%) allocated placebo (odds ratio 3.9, 95% CI 1.42-10.72, p=0.006). C-reactive protein and erythrocyte sedimentation rate declined by 50% and 28%, respectively, relative to placebo (p<0.0001, p=0.005, respectively). Swollen joint count also fell (-2.69 vs -0.53; mean difference -2.16, 95% CI -3.67 to -0.64, p=0.0058). Adverse events occurred with similar frequency in patients allocated atorvastatin and placebo. INTERPRETATION: These data show that statins can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.

McKellar GE, McCarey DW, Sattar N, McInnes IB. · Center for Rheumatic Diseases, Glasgow, Royal Infirmary, Glasgow, UK. · Nat Rev Cardiol. · Pubmed #19421244 No free full text.

Abstract: Inflammatory pathways have been implicated in the initiation and progression of cardiovascular diseases. Accelerated atherosclerosis has been described in patients with chronic inflammatory diseases, particularly rheumatoid arthritis, disproportionate to individuals' detectable traditional vascular risk factors. This finding suggests that other pathways associated with inflammation might account for increased vascular risk in such diseases. Highly specific biologic agents can precisely block the activity of cytokines generated during inflammatory cascades; the effects of these inflammatory moieties on vascular physiology and overall risk of cardiovascular events has been directly evaluated. This review summarizes key epidemiologic, physiologic and model data, which together suggest that tumor necrosis factor, a pivotal cytokine in the inflammatory cascade, is directly involved in vascular pathophysiology and that its inhibition might confer an overall advantage to the recipient. Moreover, such data obtained in chronic inflammatory diseases likely have relevance to primary atherosclerosis.

Jick SS, Choi H, Li L, McInnes IB, Sattar N. · Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington, Massachusetts 02421, USA. · Ann Rheum Dis. · Pubmed #18662929 No free full text.

Abstract: OBJECTIVE: To evaluate whether statins are associated with a protective effect on the development of rheumatoid arthritis (RA). METHODS: A nested case-control study was conducted using data from the General Practice Research Database. A study population consisting of three groups of subjects aged 40-89 years was identified: (1) patients exposed to a statin or other lipid-lowering agent (LLA); (2) patients with a diagnosis of hyperlipidaemia in the absence of lipid-lowering drug treatment and (3) a random sample of 25 000 individuals with no diagnosis of hyperlipidaemia nor a prescription for a LLA. From this population incident cases of RA and up to four controls for each case were identified, matched on age, sex, general practice, number of years of recorded history in the database and index date. The independent effects of hyperlipidaemia and statins on the development of RA were evaluated using conditional logistic regression. RESULTS: 313 cases of RA and 1252 matched controls were identified. Compared with patients with untreated hyperlipidaemia, or hyperlipidaemia treated with LLA other than statins, the adjusted odds ratio for patients with no hyperlipidaemia was 0.68 (95% CI 0.50 to 0.91). When those with hyperlipidaemia who received statins were compared with those with hyperlipidaemia who did not use statins (ie, untreated hyperlipidaemia patients or those treated with non-statin LLA) the OR was 0.59 (95% CI 0.37 to 0.96). CONCLUSION: These data provide evidence to support the hypothesis that statins may be protective against the development of RA in patients with hyperlipidaemia.

Leung BP, Sattar N, Crilly A, Prach M, McCarey DW, Payne H, Madhok R, Campbell C, Gracie JA, Liew FY, McInnes IB. · Department of Immunology, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom. · J Immunol. · Pubmed #12538717 links to  free full text

Abstract: 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.